1-phenyl-2-pyrrollidino-pentane and salts



United States Patent 0.

3,186,997 l-PHENYL-Z-PYRRULLTDHNO-PENTANE AND SALTS Ernst Seeger andAugust Kottler, Eiberach an der Risa,

Germany, assignors, by mesne assignments, to Beeliringer IngclheiinG.m.h.H., lngelheim (Rhine), Germany, a corporation of Germany NoDrawing. Filed Oct. 18, 1%2, Ser. No. 231,543 Claims priority,application Qermany, Italy 1, 1955, T 11,089; Apr. 26, 1956, T 12,153, T12,154 1 Claim. (Cl. 260--2%5.5)

This is a continuation-in-part of copending application Serial No.6,619, filed February 4, 1960, now abandoned, which in turn is acontinuation-in-part of application Serial No. 710,186, filed January21, 1958, now abandoned, which in turn is a continuation-in-part ofapplications Serial No. 654,455, filed April 23, 1957, now abandoned,Serial No. 654,456, filed April 23, 1957, now abandoned, and Serial No.630,454, filed December 26, 1956, now abandoned, the latter being inturn a continuation-in-part of application Serial No. 544,385, filedSeptember 21, 1955, now abandoned.

This invention relates to novel tertiary amines having usefulpharmacological properties and to their non-toxic, pharmacologicallyacceptable acid addition salts.

More particularly, the present invention relates to tertiary amineshaving the structural formula wherein R is selected from the groupconsisting of hydrogen and methyl,

Y is straight or branched alkyl of 3 to 4 carbon atoms,

and

n is an integer from 4 to 5, inclusive,

and their non-toxic, pharmacologically acceptable acid addition salts.The tertiary amines having the above structural Formula I may beprepared by reacting a fl-aryl-a-tertiaryamino-propionitrile of theformula wherein R and n have the same meanings as in Formula I above,with an alkyl-magnesium-halide of the formula Y-Mg-Hal (111) wherein Yhas the same meanings as in Formula I above and Hal is a halogenselected from the group consisting of chlorine, bromine and iodine. Thereaction of compound II with compound III is advantageously carried. outin the presence of a suitable inert organic solvent, such as ether orbenzene, or a solvent mixture consisting, for example, of benzene andtetrahydrofuran. The preferred method comprises refluxing the reactionmixture at the boiling point of the particular solvent medium employedat atmospheric pressure, although the reaction will also proceed atmoderately elevated temperatures below the boiling point of the solventand without reflux.

The compounds embraced by Formula I above may were added. The mixturewas separated into an aqueous amass? Patented June 1, 1965 also beprepared by reacting an oi-piperidylor a-pyrrolidyl-alkyl cyanide of theformula wherein Y and n have the same meanings as in Formula I above,with a benzyl-magnesium-halide or a p-methyL benzyl-magnesium-halide ofthe formula wherein R and Hal have the same meanings as in Formula Iabove, in the presence of an inert organic solvent, such as benzene,ether, dibutyl ether or tetrahydrofuran, acidifying the reaction mixturewith a dilute acid, preferably hydrochloric acid, to separate it into anorganic phase and an aqueous acidic phase, and separating the reactionproduct from the aqueous acidic phase.

T e a-tertiary amino-nitriles II and IV used as starting materials forthe preparation of the tertiary amines ac- ,cording to the presentinvention are readily available or 1 -phenyl-2-piperidin'o-pentane Asuspension of 48 gm. magnesium powder in 800 cc. of a mixture of benzeneand tetrahydrofuran (1:1) was added dropwise to 260 gm. benzyl chloridewhile agitating the mixture and maintaining it at a temperature of about30 C. After all of the magnesium suspension had been added and theGrignard reagent had formed,

stirring was continued and a solution of 166 gm. oc- Vpiperidino-n-valeronitrile (boiling point at 10 mm. Hg :107 C. in 300cc. of a mixture of benzene and tetrahydrofuran (1:1) was added to theGrignard reagent at a suificiently slow rate so as not to cause thetemperature of the mixture to rise above 40 C. The reaction mixture wasthen heated for three hours at 40 C. while continuing the agitation.Thereafter, agitation was continued for several hours at roomtemperature to permit the reaction to go to completion. The bulk of thebenzene-tetrahydrofur-an solvent was then removed by evaporation invacuo. Subsequently, ice was added to the evaporation residue, it wasslightly acidified with hydrochloric acid and 700 cc. benzene phase anda benzene phase. The phases were separated and the benzene phase wasshaken twice with hydrochloric acid. The acidic solutions were combinedagain and ammonia was added, whereby a liquid phase separated out whichwas separated and taken up in benzene. The benzene was evaporated bydistillation, yielding gm. of a compound of the formula "was taken up inether.

A v V 3,186,997.

. 3 v 7 having a'boiling point of108 C. at 0.4 mm. Hg. .The

' product was a colorless liquid.

The tertiary amine was converted into its hydrochloric acid additionsalt by precipitating it from solution wth ethereal-hydrochloric acid.The hydrochloride'was obtained in the formof colorless crystals havinga'melting point of 166-167 C. 7

EXAMPLE 11 y 1-phenyl-2-giiperidino-hexane Following the proceduredescribed in Example I, but using 32 gm. u-piperidino-capronitrile(boiling point at 14 mm. Hg l26128 C.) instead ofa-piperidino-pentene-(2)'-nitrile, the compound of the formula QOHFaE-GH -om E) ""A solution of 17 gm. u-piperidino-valeronitrile in ether wasadded to a Grignard reagent prepared by adding 4.8 .gm. magnesium powderand 37 gm. p-xylyl bromide to anhydrous ether, accompanied by stirring.The resulting mixture was refluxed at moderately elevated temperaturesfor two hours and was thereafter decomposed into the separate phases byadding ice and a sufficient amount of hydrochloric acid to make it reactacidic. The ethereal phase was separated and discarded, while theaqueous acidic phase was made alkalinev with ammonia. A liquid separatedout which The ether extract was evaporated to drive off the ether andthe evaporation residue was distilled in vacuo. 19.5 gm. of the compoundof the formula omom-en-om-omom V N 7 7 having a b'oiling point of1l4-116 C: at- 0.4 mm. Hg

were obtained in the form of a-colorless liquid. I

The hydrochloride of this tertiary amine, obtained in accordance Withthe method described in Example I, had

a melting point of 183 C. after recrystallization from acetone. 7

EXAMPLE 1V 1-phenyl-2-piperidino-perttrme-liydrochloride i 70 gm.1-phenyl-2-piperidino-pentane, obtained acwas then allowed to stand inthe refrigerator for about ten hours. The crystals whichprecipitatedirom "the solution during this period were filtered off on-avacuum filter and thefilter cake was recrystallized from acetone.

1 18 gm. of the colorless sulfuric acid addition salt of l' 1piperidino-pentane having a melting point lot 166 C.

were obtained. V

' EXAMPLE V 1 (p-methyl-phenyl -2-piperidino pentafie-sulfate 19 gml-(p-methyl-phenyl)-2-piperidino-pentane, obtained according to ExampleIII, weredissolved in 100 cc. ether, and then 3.6 gm. 98% sulfuric acidwere gradually added to the ether solution while stirring it. An oilysubstance separated out. The mixture was allowed to stand'in arefrigerator for a short period of time. during which the oilyprecipitate crystallized. The crystals were separated by filtration andrecrystallized from isopropanol.

(pmethyl-phenyl)-2-piperidino-pentane having a melting point of 178 wereobtained. a

' 7 EXAMPLE VI y 1 -phenyl-2-pyrrolidino 3methyl-butane A Grignardreagent was prepared by Ladding' LG grn.'f

magnesium powderto 25 .2 gm. benzyl chloride dissolved in absoluteether. A solution of 15.2 gm. a-pyrrolidino1 isovaleronitrile (boilingpoint at 237mm. Hg; 103-104 C.) in cc.'-absolute etherwasadded to theGrignard reagent dropwise, while continuouslystirring. The resultingmixture was refluxedat moderate temperatures for 1 hours whilecontinuing the agitation. Thereafter; the reaction mixture was cooledice was added, and it was made acidic by adding dilute hydrochloricacid. An

etheral phase and an aqueous acidic phase were formedi 7 thereby; Theethereal phase was separated and discarded, while the aqueous acidicphase was made alkaline with ammonia. An oily substance separated outwhich was exof the hydrochloric acid addition salt of l-phenyl-Z-tracted with ether; The ether extract was driedover sodium sulfate andwas then heated to' drive off the ether solvent. The oily residue wasdistilled in a vacuum. 17 gm. of the compound of the formula havingaboiling point of 88 Cat 0.2' mm; Hg were ob-' tained in the form ofa-colorless-liquid.

The tertiary amine thus obtained was converted into its hydrochloride bydissolving the amine'in ether aridaddi'n'g an et'heral solution ofhydrochloric acid-thereto. The

390 gm. benzyl chloride were added dropwise to 400 cc. of a mixtureconsisting of 72 gm. magnesium powder and equal parts of benzene andtetrahydrofuran. During the addition of the benzyl. chloride, carewas'taken not to allowthe temperature to rise' above 40 C. The resultingGrignard reagent was diluted with 750 cc, of a mixture of" equal partsof benzeneand 'tetrahydrofuranr 228 gm. a-pyrrolidino-valeronitrile,dissolved in a-mixture of benzene and tetrahydrofuran, were addeddropwise to the Grignard solution, taking care that the temperature ofthe reaction mixture didnot rise above 40 C. 'After all of thevaleronitrile solution had been added, the re .sulting mixture was firststirred for three hours at 40 C.

and then for some additional time at room temperature. The majority ofthe benzene-tetrahydrofuran' solventwas then removed by vacuumdistillation andthe distillation residue was divided into two phases byadding ice and hydrochloric acid until it reacted acidic. 1 liter ofbenzene was added to the two-phase system. The aqueous acidicphase wasseparated and the benzene phase was shaken twice with dilutehydrochloric acid; The aqueous hydro-- chloric acid solutionswerecombined and made alkaline withjarrimonia. An oily substanceseparated out which;

was extracted with benzene. The benzene extract was evaporated to driveoff the benzene and the residue was distilled in vacuo. 275 gm. of thecompound of the formula having a boiling point of 90-92 C. at 0.3 mm. Hgwere obtained.

The colorless crystalline hydrochloride of this amine had a meltingpoint of 134-135 C.

dinoa'sovaleronitrile, 17 gm. of the compound of the formula having aboiling point of 101 C. at 0.5 mm. Hg were obtained.

. 6 EXAMPLE XI 1-phanyI-Z-pyrrolidina-pentane sulfate 2.5 gm. 98%sulfuric acid were added to a mixture of 10.5 gm.1-phenyl-2-pyrrolidino-pentane, obtained in accordance with Example VII,and 75 cc. ether, while stirring and cooling the mixture. An oilysubstance precipitated out which solidified after standing for some timeat room temperature. For purposes of purification, the solidified oilwas recrystallized from acetone. The sulfuric acid addition salt ofl-phenyl-pyrrolidino-pentane was thus obtained in the form of colorlesscrystals having .a melting point of 102 C.

EXAMPLE XH 1-phenyl-Z-pyrr0lidino-pentane citrate A solution of 0.6 gm.citric acid in cc. isopropanol was added to a mixture of 10.5 gm.l-phenyl-Z-pyrrolidino-pentane and 30 cc. isopropano'l. The resultingmixture was heated to 40 C. for-ten minutes. Thereafter, it was cooledand 200 cc. ether were added. The mixture was allowed to stand in arefrigerator, whereby "a solid precipitated out which was recrystallizedfrom methyl ethyl ketone. 19 gm. of the citric acid addition salt of1-phenyl-2-pyrrolidino-pentane were obtained in the form of colorlesscrystals.

EXAMPLE XIII l-plzanyl-2-pyrrolidin0-pentane hydrochloride Hydrogenchloride gas was bubbled through a solution of 20 gm.1-phenyl-2-pyrrolidino-pentane in 50 cc. benzene, accompanied bystirring, until the solution was slightly acidic. Thereafter, the acidicsolution was allowed to stand for a few hours, whereby a precipitateformed. The precipitate was filtered ofr on a vacuum filter and thefilter cake was recrystallized from acetone. 17 gm. of the hydrochloricacid addition salt of 1-phenyl-2-pyrroli dino-pentane having a meltingpoint of 135 C. were obtained in the form of colorless crystals.

The following table illustrates additional tertiary amines according tothe present invention which were prepared and lists the melting and/0rboiling points, the melting point of the corresponding hydrochlorideaddition salt,

MP. of Grignard Reagent Yield EX. N0. Tertiary Amine Produced B.P., C./Hydrochlo- Acetonitrile Reagent from magnesium percent mm. Hg ride, C.and of theory 23 1-pl1enyl-2-pyrrolidino- 10510.5 134-135Z-phenyl-l-pyrrolidinon-Propyl-hromide 78 peutuue. propiomtr le. v 24l-phenyl-Z-piperidinm 100-10110. 2 163-164 Z-phenyl-l-mpendmoi do 70pentane. propiomtrile. 25 l-phenyl-2pyrrolidino- 108410,). 62-pheny1-l-pyrrohdmon-Butyl-bromide 74 hexane. proplomtnle. 26l-phenyl-Z-pyrrolidino-fi- 88/0. 2 ..do Isopropyl bromide 71methyl-butane.

The hydrochloride of this tertiary amine had a melting point of 125-126C.

EXAMPLE X J-(p-methyl-phenyl) -2-pyrr0lidin0-pentane Following theprocedure described in Example VI, but using 4.6 gm. magnesium powder,37 gm. p-xylyl bromide and 15 gm. a-pyrrolidino-valercnitrile, 17 gm. ofthe compound of the formula the nitrile and Grignard reagents used andthe yield in each case.

As previously stated and illustrated in the preceding examples, thetertiary amines according to the present invention form non-toxic,pharmacclogically useful acid addition salts. It is well known in thepharmacolgical and therapeutic arts that the non-toxic acid additionsalts of basic pharmacologically active substances do not materiallydiffer from the basic substances themselves in their pharmacologicalactivities. The acid addition salts merely provide a desirablesolubility factor. So it is with the present tertiary amines.

Typical examples of pharmacologically useful and acceptable non-toxicacid addition salts of the present tertiary amines are those formed withhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, acetic acid, propionic acid, butyric acid, valeric acid,

t t 7 oxalic acid, malonic acid, succinic acid, maleic acid, fumaricacid, lactic acid, tartaric acid, citric acid, rn'a'lic acid,benzoic'acid, phthalic'acid, cinnamic acid, salicylic acid, nicotinicacid, 2-furoic acid and the like. The particular acid addition saltsillustrated in the examples, however, have been found to be particularlysuitable for practical purposes i The compounds embraced by Formula Iabove and their non-toxic acid addition salts are useful and effectivepharmacological agents. More particularly, they exhibit a stimulatingeffect upon the central nervous system and analeptic as Well aspapaverine-like myotropic spasmolytic and hypertensive activities. I

'While we have illustrated the present invention with the aid of certainspecific embodiments thereof, it Will be readily apparent to thoseskilled in the art that the inven tion is not-limited to theseembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claim.

' We claim: 7

A compound selected from the group consisting of 1-phenyl-Z-pyrrolidino-pentane and its, non-toxic pharmacologicallyacceptable acid addition salts.

R efierences Cited by the Examiner UNITED STATES PATENTS 2,683,742 27/54'Cu si'c 260 313 7 2,711,428 '6/55 'Goodson et a1. 260293 2,824,111 2/58Heinzelman 260293 I FOREIGN PATENTS 191,869 9/57 Austria. a 627,139 7/49Great Britain, 1

OTHERREEERENCES p V Beilsteins Handbuch der Or'ganischen Chemie, vol.20, Second-Supplement (1953), page 16, System No. [3038]. i 7

, Heinzelman et 21 Journal of the American Chemical Society, vol. 75,page 3410 (1953).- V

Heinzelman et al.: Journal of the American Chemical Society, vol. 75,pages 3409 and 3411-3413 added, 1953. V

'Kadatz et al.: Arzneimittel Forschungvol. 6; page 345 1957 I V Stevens:Journal of the Chemical Society (1931'), page 2568. y V WALTER A,MODANCE, Primary Examiner. IRVING MARCUS, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,186,997 June 1, 1965 Ernst Seeger et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected belo Column 1, lines 30 to 34, right-hand portion of theformula, for "X"read Y line 62 for "bromne" read bromine column 2, lines3 to 7, right-hand portion of the formula, for "-X" read ---Y line 47,after "107 C."

insert a closing parenthesis.

Signed and sealed this 23rd day of November 1965.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attestmg Officer Commissioner ofPatents

